Asparagine depletion after pegylated E. coli asparaginase treatment and induction outcome in children with acute lymphoblastic leukemia in first bone marrow relapse:: A children's oncology group study (CCG-1941)

Purpose. Re-induction outcomes vary for children with acute lymphoblastic leukemia (ALL) and marrow relapse. We explored possible relationships among asparaginase (ASNase) activity levels, asparagine (ASN) depletion, anti-ASNase antibody titers, and response to re-induction therapy in children and adolescents with ALL and an 'early' first marrow relapse. Patients and methods. After appropriate informed consent, we enrolled children and adolescents 1-21 years old with ALL and first marrow relapse within 12 months of completion of primary therapy. Induction therapy included intramuscular pegylated ASNase on Days 2 and 16. We assessed ASNase activity, anti-ASNase antibody titers against native and pegylated (E. coli) ASNase, and amino acid levels of asparagine (ASN) and glutamine (GLN) on Days 0, 14, and 35 of re-induction. Results. Ninety-three patients were at least partially assessable. Among 21 patients with M1 marrow status at Day 35, the median Day 14 ASN level was < 1 mu M. This is significantly lower than the median Day 14 ASN level of 4 mu M in the group of patients with M3 marrow at Day 35. Neither Day 0 nor Day 35 antibody titers predicted ASNase enzymatic activity level on Day 14. Surprisingly, Day 14 ASNase activity did not predict serum ASN level on Day 14. However, Day 0 and Day 35 anti-native ASNase antibody titers, and Day 0 anti-PEG ASNase antibody titers correlated positively with Day 14 serum ASN levels as one might expect from neutralizing antibody. Day 35 anti-PEG ASNase antibody titers did not. Conclusions. Patients with greater ASN depletion were more likely to achieve second remission in the context of six-drug therapy.